Design and Synthesis of Sulfate Oligo-Idose Analogs: Potential Heparan Sulfate Glycomimetics

Abstract

The structural microheterogeneity of heparan sulfate (HS) is intrinsically governed by repeating disaccharide units, sulfation patterns, uronic acid composition and conformation plasticity of L-Iduronic acid. These factors synergistically promote HS-mediated biological activities. Despite rapid progress in synthesizing structurally defined HS oligosaccharides, how disaccharide heterogeneity directly contributes to HS biological functions is not well studied. Recently, we have shown that homo-oligosaccharides with different sulfation patterns can modulate the selectivity and specificity of growth factors and chemokines. Motivated by these results, we have synthesized L-idose-based homo-oligosaccharides with a wide range of sulfation patterns to fine-tune the specific HS-protein interactions. HS mimics were synthesized from L-idose thiophenol donor and β-L-idopyranosyl acceptor building block. We installed oligosaccharides using [2+2] glycosylation strategy. These mono, di and tetrasaccharides are subjected to divergent strategy, where selective protecting groups were removed and sulfated. So far, we successfully synthesized mono, disaccharides with partial and fully sulfated ligands and currently optimizing the synthesis of higher oligosaccharides. Once we have all 16 compounds in hand, we are planning to establish structure-activity relationships with heparin-binding proteins, particularly with growth factors and chemokines.